This Pilot Scale Library (PSL) proposal describes the construction of libraries containing novel structures and their submission to the NIH Molecular Libraries Small Molecule Repository (MLSMR). Projects are chosen to maximize (1) the novelty of the submitted structures, as determined by examination of the PubChem database and through an in-house diversity analysis, (2) the likelihood that the libraries proposed will be useful in screening by designing them in analogy with known bioactive agents, and (3) efficiency, by designing syntheses based on established methods for scaffold preparation (generally invented in the Pi's laboratory) combined with straightforward diversification schemes. Once assembled, libraries will be purified using mass directed fractionation techniques and submitted to the Molecular Libraries Small Molecule Repository. The libraries are organized in five major themes. They are (1) alkaloid-like libraries derived from Lewis acid promoted reactions of alkyl azides that afford complex ketones that are subsequently converted to carbamates, amines, indoles, or other heterocyclic products, (2) libraries based on a recently reported class of twisted lactams, (3) libraries inspired by synthetic routes toward marine alkaloids of the cylindricine/lepadiformine class, (4) haouamine A analogs, and (5) libraries inspired by the natural product martinelline and consensus structures of nuclear hormone receptors. PUBLIC HEALTH RELEVANCE: The goal of this Pilot Scale Library proposal is to generate high-quality collections of novel chemical compounds with properties consistent with biological activity. Following submission of these compounds to the Molecular Libraries Small Molecule Repository, they will be screened in numerous assays relevant to human health. Compounds found to be active in these screens can lead to probes that will enhance biomedical research.